1. Uropathogenic Escherichia coli invades bladder epithelial cells by activating kinase networks in host cells
- Author
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Joon-Hyung Kim, Yehia Daaka, Allyson E. Shea, and Wan-Ju Kim
- Subjects
0301 basic medicine ,Host–pathogen interaction ,Urinary Bladder ,030106 microbiology ,mTORC1 ,Biology ,urologic and male genital diseases ,medicine.disease_cause ,Microbiology ,Biochemistry ,mTORC2 ,03 medical and health sciences ,medicine ,Animals ,Humans ,Uropathogenic Escherichia coli ,Secretion ,Molecular Biology ,Escherichia coli ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Epithelial Cells ,Cell Biology ,female genital diseases and pregnancy complications ,ErbB Receptors ,030104 developmental biology ,Culture Media, Conditioned ,Host-Pathogen Interactions ,Urinary Tract Infections ,Signal transduction ,Protein Kinases ,Signal Transduction - Abstract
Uropathogenic Escherichia coli (UPEC) is the causative bacterium in most urinary tract infections (UTIs). UPEC cells adhere to and invade bladder epithelial cells (BECs) and cause uropathogenicity. Invading UPEC cells may encounter one of several fates, including degradation in the lysosome, expulsion to the extracellular milieu for clearance, or survival as an intracellular bacterial community and quiescent intracellular reservoir that can cause later infections. Here we considered the possibility that UPEC cells secrete factors that activate specific host cell signaling networks to facilitate the UPEC invasion of BECs. Using GFP-based reporters and Western blot analysis, we found that the representative human cystitis isolate E. coli UTI89 and its derivative UTI89ΔFimH, which does not bind to BECs, equally activate phosphatidylinositol 4,5-bisphosphate 3-OH kinase (PI3K), Akt kinase, and mTOR complex (mTORC) 1 and 2 in BECs. We also found that conditioned medium taken from UTI89 and UTI89ΔFimH cultures similarly activates epidermal growth factor receptor (EGFR), PI3K, Akt, and mTORC and that inhibition of EGFR and mTORC2, but not mTORC1, abrogates UTI89 invasion in vitro and in animal models of UTI. Our results reveal a key molecular mechanism of UPEC invasion and the host cells it targets, insights that may have therapeutic utility for managing the ever-increasing number of persistent and chronic UTIs.
- Published
- 2018
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